St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK.
Dermatology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
Exp Dermatol. 2020 Jun;29(6):520-530. doi: 10.1111/exd.14096. Epub 2020 May 25.
Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997.
To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019.
Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs61) and c.1213delA (p.Arg411Glufs22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections.
These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.
桥粒是细胞间黏附的钙黏蛋白介导的黏附复合物，将中间丝锚定在细胞膜上，是组织在机械应力下强黏附所必需的。桥粒的一个特定组成部分是桥粒斑蛋白 1（PKP1），它主要在表皮的棘层表达。PKP1 的常染色体隐性失活突变导致外胚层发育不良-皮肤脆弱（EDSF）综合征，这是 1997 年首次报道的桥粒的第一个遗传性孟德尔疾病。
研究 2 例 EDSF 综合征新病例，并对 1997 年至 2019 年致病性 PKP1 突变进行文献复习。
PKP1 的 Sanger 测序发现了两个新的纯合移码突变：c.409_410insAC（p.Thr137Thrfs61）和 c.1213delA（p.Arg411Glufs22）。对 18 例经证实的双等位基因 PKP1 基因突变进行了全面分析，但对 1 例嵌合病例或 6 例缺乏基因突变研究的病例没有进行分析。所有致病性种系突变均为功能丧失（剪接位点、移码、无义），突变位于内含子 1 公认的接受剪接位点（c.203-1>A 或 G>T），为反复出现的发现。皮肤脆弱和指甲受累见于所有受影响的个体（18/18），大多数病例表现为手掌足底角化过度（16/18）、脱发/少毛症（16/18）和口周皲裂/唇炎（12/15；在 3 例中未予评论）。在一些个体中进一步观察到瘙痒、生长不良伴身高/体重百分位低、毛囊角化过度、少汗、行走困难、牙发育不良和反复胸部感染。
这些数据扩展了 EDSF 综合征的分子基础，并有助于定义这种桥粒皮肤病的原型和可变表现的谱。
